Osteoporotic fractures are major public health problems that have been associated with low vitamin D levels. Previous data strongly suggest that doses of vitamin D = 700 IU/day reduce fractures and possibly falls. Basic and small clinical trials suggest that omega-3 fatty acids may also have beneficial skeletal effects, but effects on fractures are not known. Large primary prevention trials with high daily doses of vitamin D and/or omega-3 fatty acids in general populations (i.e., unselected for disease risk) are lacking. We propose an ancillary study to the VITAL study, a large, randomized, double-blind, placebo-controlled trial of vitamin D (in the form of vitamin D3 [cholecalciferol]) and/or marine omega-3 fatty acid (eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA]) supplements, to advance knowledge and test the effects of vitamin D3 (2000 IU/d) and/or fish oil (EPA+DHA, 1g/d) for primary prevention of fractures, bone loss, falls, and frailty. Growing enthusiasm for supplemental vitamin D to support bone health, and use of fish oil, which may also have skeletal effects, underscores the urgent need for a timely initiation of this ancillary study in conjunction with the newly funded VITAL parent study (U01CA 138962). The proposed ancillary study will include 20,000 women and men (>age 65 and 60, respectively) from the 5-year, NIH-sponsored, parent VITAL trial and a sub-cohort from that trial of 700 participants from Clinical and Translational Science Centers (CTSCs) in Boston, Chicago, Houston, and San Francisco to critically test these hypotheses: Primary Aims: In the VITAL cohort, will vitamin D3 and/or EPA+DHA reduce incident a) total fractures and b) hip or non-vertebral fractures? Secondary Aims: In the CTSC sub-cohort, will vitamin D3 and/or EPA+DHA reduce bone loss of the spine, hip, and total body, as assessed by Dual X-ray Absorptiometry at baseline and year 2 and do effects vary with (a) baseline and follow up blood levels of these nutrients, (b) gender, (c) race/skin pigmentation, and (d) body mass index? Tertiary Aims: In the VITAL cohort, will Vitamin D3 and/or EPA+DHA supplementation a) reduce the risk of falls as assessed by annual questionnaires and b) reduce frailty as determined by the questionnaire- based frailty index? Baseline and follow-up blood collections will be matched for season by month to prevent seasonal bias for vitamin D levels. In order to complete pre-randomization measurements among participants in the CTSC sites, it is essential that this ancillary study be undertaken in parallel to the parent VITAL trial placebo run-in to get baseline and follow-up measurements, which is scheduled to begin in mid-2010. This time-sensitive ancillary study will rigorously test the role of these nutritional supplements in improving skeletal health and will provide positive or informative null results on the effects of vitamin D and omega-3 fatty acids on fractures, bone density, falls, and frailty. We expect that findings from this ancillary study will inform clinical practice on whether high daily dose vitamin D and/or fish oil reduces the burden of age-related increases in fractures, which would result in widespread public health benefits.